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Charles was born in the Kingdom of Buganda, the southern part of modern Uganda, and served as a page and later major-domo in the court of King Mwanga II. As part of the king's effort to resist foreign colonization, the king insisted that Christian converts abandon their new faith, and executed many Anglicans and Catholics between 1885 and 1887, many of whom were officials in the royal court or otherwise very close to him, including Lwanga.

The persecution started in 1885. After a massacre of Anglican missionaries, which included Bishop James Hannington, the leader of the Catholic community, Joseph Mukasa – who was then major-domo of the court, as well as a lay catechist—reproached the king for the killings, against which he had counseled him. Mwanga had Mukasa beheaded and arrested all of his followers. This took place on November 15th. The king then ordered that Lwanga, who was chief page at that time, take up Mukasa's duties. That same day, Lwanga sought baptism as a Catholic by a missionary priest.

On May 25, 1886, Mwanga ordered a general assembly of the court while they were settled at Munyonyo, where he charged two of the pages, whom he then condemned to death. The following morning, Lwanga secretly baptized those of his charges who were still only catechumens. Later that day, the king called a court assembly in which he interrogated all present to see if any would renounce Christianity. Led by Lwanga, the royal pages declared their fidelity to their religion, upon which the king ordered them bound and condemned them to death, directing that they be marched to the traditional place of execution. Two of the prisoners were executed on the march there.

When preparations were completed and the day had come for the execution on June 3rd, Lwanga was separated from the others by the Guardian of the Sacred Flame for private execution, in keeping with custom . As he was being burnt, Charles said to the Guardian, "It is as if you are pouring water on me. Please repent and become a Christian like me."

Twelve Catholic boys and men and nine Anglicans were then burnt alive (another Catholic, Mbaga Tuzinde, was speared to death for refusing to renounce Christianity, and his body was thrown into the furnace to be burned along with those of Lwanga and the others[3]). The ire of the king was particularly inflamed against the Christians was because they refused to accede to demands to participate in sexual acts with him.[4] Charles Lwanga, in particular, had protected the pages from King Mwanga's sexual advances.[5] The executions were also motivated by Mwanga's broader efforts to avoid foreign threats to his power. According to Assa Okoth, Mwanga's overriding preoccupation was for the "integrity of his kingdom," and perceived that men such as Lwanga were working with foreigners in "poisoning the very roots of his kingdom". Not to have taken any action could have led to suggestions that he was a weak sovereign.[6]

Charles Lwanga and the other Catholics who accompanied him in death were canonized in 1964 by Pope Paul VI during a pastoral visit to Uganda.[7] Although the Anglicans could not be canonized, they were named "with the others, also deserving mention" for enduring "death for the name of Christ".[8]